PB0528 - Immediate acting Factor VIII inhibitors in acquired and congenital hemophilia A: Clinical importance and relevance.

Background: FVIII-inhibitors are generally time-temperature dependent. However, there exists presence of specific FVIII-inhibitors in some congenital-persons-with-hemophilia-A (PwHA) with absence of time-dependent inactivation kinetics similar to those seen in acquired-hemophilia A.

Aims: To better understand inhibitory kinetics by IgG-subclass of immediate-acting-inhibitors(IAI) in congenital PwHA and assess the clinical situations where IAIs develop.

Methods: 306 congenital PwHA were included(140:inhibitor-negative, 56 low-titer, 68 high-titer, 42 immediate-acting FVIII-inhibitors) along with 95 healthy-controls,5 non-hemophiliac lupus-anticoagulant(LA) positive and 5 acquired-hemophilia A patients. Periodic samples from 20PwHA with inhibitors on immune tolerance induction(ITI) were also included. Tests done included one-stage-factor assay, Nijmegen-modified-Bethesda assay, LA and FVIII inhibitors by ELISA with IgG subtyping. Proforma of all past bleeds, treatment and surgeries was filled for 30 PwHA with IAIs.

Results: The IgG-subclass in different groups is shown in Figure1. Interestingly, the subclass pattern of acquired-hemophilia A and congenital-PwHA with IAIs was the same: IgG2+IgG4. Among these, 90% developed IAI post-major surgery or after severe bleeds like intracranial bleeds, ITI which involves continuous FVIII infusions. Out of the 20 patients on ITI, 10 had ITI success with normal IgG1/IgG4 subclass with no IAIs. Among patients who had < 50% reduction in inhibitor-titer after 6-12 months, the time-dependent FVIII-inhibitors were converted to IAIs (IgG2 + IgG4). In 5 of these patients, Rituximab was given, 5 attained ITI success with one relapse. The IgG profile on one such patient (Figure2) showed that the time dependent IgG4 subclass converted to the IAI:IgG2+ IgG4 subclass which after Rituximab was converted back to IgG4/IgG1 and was eventually negative for inhibitors.

Conclusion(s): Immediate-acting-inhibitors have a subclass similar to that of acquired-hemophilia A and the observation that patients on ITI with no reduction in titers develop these IAI suggests that these IAI cannot be overlooked and may have clinical significance.